Immunoregulatory abnormalities have been shown to exist in a wide variety of "autoimmune" and chronic inflammatory diseases, including systemic lupus erythematosis, rheumatoid arthritis, type 1 diabetes mellitus, inflammatory bowel disease, multiple sclerosis and contact sensitivity. Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates.
Similarly, in transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to the rejection of the transplanted organ.
The end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Antiinflamatory agents such as NSAID's and corticosteroids act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb from infection as they are from their autoimmune disease.
Accordingly, an object of the present invention is to provide various thiazole derivatives as immunoregulants which will (1) restore the normal balance of the help-and-suppression mechanism of the immune system by acting at an earlier point than the anti-inflammatory agents and (2) induce specific long-term transplantation tolerance through a suppressor cell circuit without increasing the body's susceptibility to infection.
Another object of the present invention is to provide pharmaceutical compositions for administering the active compounds as immunoregulants.
Still a further object of this invention is to provide a method of controlling transplant rejection, autoimmune and chronic inflammatory diseases by administering a sufficient amount of one or more of the active compound in a mammalian species in need of such treatment.
Finally, it is the object of this invention to provide chemical processes for the preparation of the active compounds.